Terminal modified polyoxyalkylene derivatives have recently been engaging attention as an important carrier for drug delivery systems in pharmaceutical fields. As the polyoxyalkylene derivatives which are starting materials to be used on this occasion, there have been known monofunctional compounds having one hydroxyl group, which are obtained by addition polymerization of an alkylene oxide to an aliphatic alcohol or an aromatic alcohol, and multifunctional compounds having two or more hydroxyl groups, which are obtained by addition polymerization of an alkylene oxide to a polyhydric alcohol such as glycerin or diglycerin. Particularly, in the case of the multifunctional derivatives, a large number of a drug can be introduced into one molecule and it becomes possible to increase the concentration in blood. Moreover, since the multifunctional derivatives exhibit gel performance through crosslinking the oxyalkylene chains having hydrophilicity at many points, they have been used in applications as sealant materials such as adhesion inhibitors and wound dressing agents. For these reasons, trifunctional and tetrafunctional polyoxyalkylene derivatives have become currently important materials indispensable in pharmaceutical fields.
JP-A-11-335460 proposes a method for producing an oxirane compound having one hydroxyl group wherein metal sodium, metal potassium, or an alcohol solution of the raw material is used as an alkali catalyst for obtaining a highly pure oxirane derivative. In the production of the trifunctional and tetrafunctional polyoxyalkylene derivatives, there is known a method of using glycerin or diglycerin as a starting material, respectively, and subjecting an alkylene oxide to addition reaction using the alkali catalyst. In general, among the alkali catalysts, the use of metal sodium or metal potassium results in low contamination of water and is suitable for the production of a highly pure oxirane derivative but these alkali catalysts show low solubility in glycerin and diglycerin and hence it is impossible to add a necessary amount of the catalyst for producing a high-molecular-weight compound. In this case, an alkali catalyst such as potassium hydroxide, sodium hydroxide, sodium methoxide, or potassium t-butoxide is employed.
A problem on the production is that, when the alcohol derived from the catalyst and water contained in the raw material remain at the start of the reaction, the alkylene oxide is added thereto to form, as by-products, monofunctional and difunctional impurities having one and two hydroxyl groups, respectively, which have molecular weight lower than that of the objective compound. Usually, in order to suppress the formation of these impurities as by-products, water removal or alcohol removal is carried out but, in the production of the trifunctional or tetrafunctional polyoxyalkylene derivative, since glycerin or diglycerin as the raw material has a high viscosity, it is difficult to remove water or the alcohol by evaporation. In this case, as a means for decreasing the viscosity, it is considered to carry out the water removal and alcohol removal at higher temperature but self-condensation of glycerin or diglycerin as the raw material occurs owing to the alkaline conditions to form polyglycerin as a by-product in some cases. When the alkylene oxide is added to polyglycerin, tetrafunctional and hexafunctional polyoxyalkylene derivatives having molecular weight higher than that of the objective compound are formed as by-products.
Moreover, as the addition reaction of the alkylene oxide proceeds, the viscosity of the reaction liquid generally increases. Therefore, at the time when it is intended to obtain a high-molecular-weight objective compound, there is a case where the reaction system becomes heterogeneous owing to the high viscosity, polydispersity is deteriorated, and stirring becomes impossible in some cases. In order to avoid the situation, the dilution with an aprotic solvent such as a hydrocarbon solvent is effective but there is a case where a difunctional impurity derived from water contained in the aprotic solvent is formed as a by-product, depending on the amount and timing for dilution.
As above, when monofunctional and difunctional low-molecular-weight impurities and tetrafunctional and hexafunctional high-molecular-weight impurities having molecular weight different from the objective molecular weight, which are formed as by-products in the production, are present in a large amount, a heterogeneous polyoxyalkylene derivative is formed. In the case where the heterogeneous polyoxyalkylene derivative is used, in the drug delivery system field, there is a concern that design evaluation of drug carriers becomes difficult and expected performance of pharmaceuticals cannot be exhibited. On the other hand, in the field of the sealant materials such as adhesion inhibitors and wound dressing agents, since the prediction of gel crosslinking points becomes difficult, there is a concern that objective gel performance cannot be exhibited. There have not yet been obtained a highly pure and high-molecular-weight polyoxyalkylene derivative not containing high-molecular-weight impurities and low-molecular-weight impurities and a producing method thereof, which address solution of these problems.